Cephalosporin and Formulations
Cephalosporins are beta lactam antibiotics that are commonly used in bacterial infections. Like other beta lactam antibiotics they show bactericid effect. The bacterial effect of cephalosporins is based on the inhibition of the synthesis of the bacteria cell wall. They inhibit cell wall synthesis by specifically binding to penicillin binding proteins (PBPs) which are present in the inner side of bacteria cell wall. As a result of inhibiting the cell wall synthesis related to PBPs, cephalosporins cause cell fractionation with the help of autolysins in the cell wall.
The formulations comprising cephalosporin group antibiotic can also be produced in the effervescent form, which is easy and safe to use for the patient and can provide the therapeutic activity and bio-availability that are provided by oral and suspension dosage forms.
For the preparation of the cephalosporin antibiotics in this dosage form, some methods are suggested in the prior art. These are dry granulation, wet granulation and dry blending methods. For instance, the patent numbered in WO2008057058 discloses the dry granulation method for the production of an antibiotic of cephalosporin group as active agent in solid dosage form. It is known that cephalosporins have a problem of wettability. Most of the medicaments included in this group are highly hydrophobic, thus they do not readily dissolve in water. Moreover, it is also known that cephalosporin antibiotics exhibit an unstable behavior upon contact with water. For these reasons, in the prior art dry granulation method is used in the preparation of the formulations comprising an antibiotic of cephalosporin group.
However, when dry granulation method is used for preparation of the formulation comprising a cephalosporin antibiotic in the form of a water dispersible dosage form, for example effervescent form, instead of solid oral dosage form, for example tablet; it is seen that harder and less porous granules are obtained. Having a harder and less porous structure of the granules can lead to obtaining dosage forms that do not homogeneously dissolve in water, for instance the agglomeration is observed in the obtained suspension or the granules forming the suspension precipitate in a short time. Therefore, these granules disperse in the water in such a way that the obtained suspension is agglomerated.
Wet granulation method that is suggested as an alternative is not preferred since effervescent acid and base give an effervescent reaction upon contact with water while they are wetted by aqueous granulation solutions and consequently carbon dioxide gas evolution is observed in the production process. Furthermore, carbon dioxide gas evolution resulting from the reaction of effervescent acid and base during the granulation prevents formation of that desirable effervescent reaction that should be obtained during the use of the final product. Therefore, this case causes a decrease in the absorption and bioavailability of cephalosporin antibiotic since the sufficient amount of carbon dioxide, which provides absorption of the active agent by increasing its permeability, is not given off.
As is seen, new approaches are needed for developing production methods of effervescent formulations comprising cephalosporin antibiotics.
As a result of the studies toward this requirement, the inventors have developed new formulations by using wet granulation method wherein formulations prepared according to the process of present invention are readily soluble and homogeneously dispersible in water; have high bioavailability and form a fluent and smooth suspension upon dispersion in water.
One aspect of said formulation is that the granulation solution that is used for preparation of formulations according to present invention comprises water in an amount in the range of 5-25%, preferably in the range of 8-20%, more preferably in the range of 10-18% and a pharmaceutically acceptable organic solvent.
In addition to water and organic solvent granulation solution may further comprise at least one pharmaceutical excipient, preferably a binder.
The inventors have surprisingly found that effervescent formulations, that are prepared by using the granulation solution comprising water in an amount in the range of 5-25%, preferably 8-20%, more preferably 10-18% by weight, have sufficiently hard and porous structure; are readily soluable; provide fluid and smooth suspension upon dispersion in water and have high bioavailability.
Second Generation Cephalosporins
Second generation cephalosporins indicate antibacterial effect on both gram positive and gram negative bacteria and have a wider gram negative spectrum compared to first generation cephalosporins. At the same time they are resistant to beta lactamase.
Antibiotics such as cefoxitin, cefamandol, cefotetan, cefuroxime, cefprozil and cefaclor are included in second generation cephalosporin group. These antibiotics of cephalosporin group are agents which are commonly used in the treatment of upper and lower respiratory diseases, sinusitis and otitis.
Formulations comprising antibiotic of second generation cephalosporin group are commonly present in form of oral tablet, oral suspension and capsule. However, solid dosage forms, wherein large amounts of antibiotic are formulated with the excipients, have a big size and this makes their use inconvenient for the patients. For that reason, as an alternative effervescent forms, which are reliable and easy to use for the patient, which are able to provide the therapeutic effect and bio-availability provided by oral suspension dosage form, are suggested.
In the prior art, it is known that at least one acid and one base are required for the preparation of effervescent formulations. Effervescent base reacts with effervescent acid in an aqueous medium and leads to evolution of carbon dioxide gas. The carbon dioxide gas evolution with bubbling provides rapid dispersion of the effervescent form in water and dissolution of the active agent easily. At the same time, carbon dioxide released as a result of effervescent reaction provides a higher absorption of the active agent by widening the intercellular space and thus increases bioavailability.
However, since the appropriate acidity is not maintained while using conventional effervescent formulations comprising an antibiotic of second generation cephalosporin group, effervescent base cannot react with acid efficiently and sufficient carbon dioxide gas evolution cannot be provided. This case makes the dissolution of antibiotic difficult and leads to decrease in the absorption and bioavailability.
As is seen, it is necessary to develop new formulations in order to provide that drugs in effervescent form comprising antibiotic of second generation cephalosporins easily dissolves upon contact with water, maintain acidity of the medium at optimum level and accordingly have a high absorption and bioavailability.
The inventors have surprisingly found that the problems in the prior art can be solved by the effervescent formulations developed in accordance with the present invention.